Epigenetic Changes May Provide ‘Novel Insights’ on Lung Cancer in Never-Smokers

DNA methylation patterns “could provide novel insights into the underlying mechanisms of lung cancer” in people who never smoked, according to a new study.

Mohammad Rahman, MD, ScD, MPH, of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, and colleagues conducted the study and published their findings in Thorax. It was important to conduct the study because the etiology of lung cancer among people who have never smoked “remains elusive, despite 15% of lung cancer cases in men and 53% in women worldwide being unrelated to smoking,” Dr. Rahman and colleagues explained.

However, epigenetic changes, such as DNA methylation, have “emerged as potential drivers” of lung cancer in people who have never smoked. Dr. Rahman and colleagues aimed to address the knowledge gap on the topic, because “few prospective epigenome-wide association studies, primarily focusing on peripheral blood DNA [methylation] with limited representation of never-smokers, have been conducted.”

Dr. Rahman and colleagues conducted a nested case-control study that included 80 people with lung cancer who never smoked and 83 people without lung cancer who never smoked. The participants were from the Shanghai Women’s Health Study and Shanghai Men’s Health Study. The researchers measured DNA methylation in prediagnostic oral rinse samples using the Illumina MethylationEPIC array. They initially conducted an epigenome-wide association study to identify differentially methylated positions associated with lung cancer in the discovery sample of 101 participants. The study authors further evaluated the top 50 differentially methylated positions in a replication sample of 62 participants. The results were pooled using fixed-effect meta-analysis.

The researchers identified three differentially methylated positions that were significantly associated with lung cancer at an epigenome-wide significance level of P<8.22×10⁻⁸.

The differentially methylated positions were:

• cg09198866 (MYH9; TXN2)
• cg01411366 (SLC9A10)
• cg12787323

When the investigators examined the top 1000 differentially methylated positions, they found “significant enrichment in epithelial regulatory regions and their involvement in small GTPase-mediated signal transduction pathways.” The study also identified GrimAge acceleration as a risk factor for lung cancer (odds ratio, 1.19 per year; 95% CI, 1.06-1.34).

“While replication in a larger sample size is necessary, our findings suggest that DNA [methylation] patterns in prediagnostic oral rinse samples could provide novel insights into the underlying mechanisms of lung cancer in never-smokers,” Dr. Rahman and colleagues concluded.

Source: Thorax